The overall goal of this grant is to define the physiological and cellular mechanisms responsible for the regression of the primate corpus luteum at the termination of the nonfertile menstrual cycle as well as to understand the mechanisms by which the lifespan of the corpus luteum is prolonged during early pregnancy. Results of our previous investigations have indicated that there is a critical period during the midluteal phase of the menstrual cycle that is characterized by heightened dependency of the corpus luteum upon LH. The overall goal of the current proposal is to elucidate the mechanisms and cellular correlates responsible for the diminished sensitivity of the corpus luteum to LH, using the cynomolgus macaque as an experimental model. In Specific Aim 1, we will use a combination of in vivo and in vitro procedures to directly assess the intracellular signaling systems as a function of luteal age to determine if changes in the responsiveness of protein kinase A and/or protein kinase C pathways are altered as the corpus luteum ages. Included in this Specific Aim are studies to determine if the PKA and PKC signaling systems differentially regulate the expression of mRNAs involved in steroid production by the corpus luteum and whether the effects of these signaling systems on RNA expression are due to changes in transcription and/or RNA stability. In Specific Aim 2, we will pursue our preliminary finding that there appear to be major alterations in the expression of nuclear transcription factors that accompany luteinization and aging of the corpus luteum. In particular, we will determine if the corpus luteum expresses a variant form of CREB that renders this major transcription factor inactive. We will also investigate the expression of other transcription factors that are regulated by the PKA and PKC signaling systems to determine if there are age-dependent alterations in the expression of these proteins in the corpus luteum. In Specific Aim 3, we will test the hypothesis that the physiological signal by which the corpus luteum is rescued during early pregnancy is a switch from pulsatile gonadotropin secretion to continuous exposure of the corpus luteum to gonadotropin. In the final Specific Aim, we will determine if the secretion of vascular endothelial growth factor (VEGF) by the corpus luteum is under gonadotropic control and whether the secretion of this angiogenic protein diminishes as the luteal phase progresses. In addition to providing important basic information regarding the functioning of the primate corpus luteum, the studies proposed herein may provide novel information regarding the pathophysiology of altered functioning of the corpus luteum in humans such as the short lutel phase and the inadequate luteal phase, both of which are thought to contribute to infertility and early gestational losses. In addition, our studies on VEGF may shed new information regarding the cause of the life-threatening changes in body fluid homeostasis that accompanies severe ovarian hyperstimulation syndrome.